Advances in the treatment of platinum resistant epithelial ovarian cancer: an update on standard and experimental therapies

ABSTRACT

Introduction: Platinum-resistant ovarian cancer (PROC) is broadly defined as disease recurrence within 6 months of completing platinum-based chemotherapy, either in the primary or recurrent setting. Although there is significant heterogeneity, PROC is generally associated with poor outcomes and low response rates to standard chemotherapy. There have been novel developments in therapeutics for PROC based on biomarkers and a more nuanced understanding of DNA repair and immunologic pathways.

Areas covered: This review provides a summary of standard of care and experimental therapies for patients with PROC. Recent advances in our understanding of the DNA damage response and immunobiology of ovarian cancer have paved the way for single agent and combinatorial strategies involving PARP inhibitors, cell cycle checkpoint inhibitors, and immune checkpoint inhibitors to overcome PARP resistance, capitalize on high replication stress, and promote effective anti-tumor immunity, respectively. Furthermore, novel agents including antibody drug conjugates, bispecific antibodies, and recombinant fusion proteins show promise as experimental treatment options.

Expert opinion: Standard and experimental treatment options available to patients with PROC have expanded. Testing for BRCA status, tumor mutational burden, and mismatch repair deficiency is recommended to guide therapy. Clinical trial participation is strongly encouraged with a focus on biomarker-driven trials targeting specific patient populations. Novel approaches such as ADCs, bispecific antibodies, targeting the GAS6/AXL and Notch pathways, and oncolytic virotherapy show considerable promise as emerging therapies.

KEYWORDS:

• Ovarian cancer
• platinum-resistance
• angiogenesis inhibitors
• antibody drug conjugate
• bispecific antibodies
• immune checkpoint inhibitors
• poly(adenosine diphosphate ribose) polymerases inhibitors

Article highlights

• Platinum-resistant recurrent ovarian cancer (PROC) has modest response rates to standard cytotoxic chemotherapy but this is augmented by anti-angiogenic agents (addition of bevacizumab is FDA approved in this setting).

• Several FDA-approved Poly(Adenosine Diphosphate Ribose) Polymerase (PARP) inhibitors (Olaparib, Rucaparib, and Niraparib) demonstrate efficacy in PROC but only in patients with BRCA-mutated tumors.

• PARP inhibitor resistance may be overcome by combinations with PI3K (alpelisib) and VEGFR (cediranib) inhibitors, which induce ‘BRCAness’ by inhibiting homologous recombination.

• Cell cycle checkpoint inhibitors (e.g., Adavosertib (WEE1 inhibitor) and berzosertib (ATR inhibitor)) leverage on the high replicative stress seen in high-grade serous ovarian cancer, especially when used in combination with cytotoxic chemotherapy or PARP inhibitors.

• Immune checkpoint inhibitors as monotherapy exhibit limited activity but ‘immunologic priming’ (i.e. transforming ‘cold tumors’ into ‘hot tumors’) using combination strategies with chemotherapy, PARP inhibitors, other immunotherapy agents, anti-angiogenic therapies, and epigenetic therapy may promote effective anti-tumor immunity (e.g., TOPACIO/KEYNOTE-162 investigating combination of niraparib and pembrolizumab).

• Antibody drug conjugates, which consist of an antibody specifically directed against a tumor-antigen conjugated through a molecular linker with a cytotoxic agent, and bispecific antibodies, which connect cytotoxic T-cells to a tumor cell independent of T-cell receptor specificity, costimulation, or peptide antigen presentation, are promising strategies that are currently under investigation in PROC (e.g., REGN4018 navicixizumab).

• The GAS6/AXL pathway is a promising target in PROC (e.g., AVB-SB-500).

• Agents targeting the Notch pathway as well as oncolytic virotherapy are emerging therapies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.